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"Appendix A: Models of Pain."
Recognition and Alleviation of Pain in Laboratory Animals.
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appendix
A
Models of Pain
INTRODUCTION
Pain can be characterized by its duration (from momentary to chronic),
location (e.g., muscle, viscera), or cause (e.g., nerve injury, inflammation).
Characterization of pain by duration may be arbitrary (i.e., when does pain
become chronic?), but is useful because most significant human pain condi-
tions are long-lasting, whether referred to as persistent or chronic.
Numerous animal models exist for the exploration of mechanism(s)
and mediators of persistent pain in particular. The principal rationale for
developing and using such models is that the sources and mechanisms of
momentary pain differ significantly from those of persistent pain. Knowl-
edge of these mechanisms is necessary to address the second objective of
such studies, namely the development of (usually) pharmacological strate-
gies for targeted, improved pain management.
Table A-1 presents commonly used models of persistent pain in animals
and the subsequent sections provide an overview of response measures
and other features of these models. Most of the models were developed
in rodents (rats or mice), unless otherwise specified, and behavioral and
other response measures are described for these species alone. Momentary,
stimulus-evoked pain is not discussed because stimulus duration is typically
short, responses are generally reflexive in nature (e.g., tail withdrawal), and
the stimulus intensity is not injurious to tissue. Animal models of momen-
tary pain are fully described in a comprehensive review by LeBars and
colleagues (2001).
143

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146 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
ANIMAL MODELS OF PERSISTENT PAIN
Inflammatory Pain Models
Rodent hindpaw inflammation is a commonly used model of persistent
inflammatory pain in which noxious stimuli are applied to the glabrous
(thermal) or glabrous and hairy (mechanical) skin of the hindpaw. Response
measures are typically hindpaw withdrawal latency to heat (seconds) or
mechanical withdrawal threshold (g or mN). Once baseline response mea-
sures have been determined, an inflammogen is injected into either the
dorsal hairy or ventral glabrous skin and withdrawal responses are assessed
over time (hours to days). Post-treatment response measures are hyper-
algesic, meaning that response latency to heat is faster and mechanical
withdrawal thresholds (typically assessed using von Frey-like nylon mono-
filaments, each of which has a different bending force) are lower. Edema,
which is also a consequence of such an injection, is greatest after the injec-
tion of carrageenan (or carrageenan plus kaolin) and least following com-
plete Freund’s adjuvant (CFA). The nature and duration of hyperalgesia differ
between the inflammogens—some produce greater thermal hyperalgesia
and others greater mechanical hyperalgesia. The hyperalgesia produced by
carrageenan is typically assessed over 4 to 6 hours but can persist more than
24 hours, whereas that produced by CFA peaks at 1 to 2 days, although it
may remain present for more than 1 week, during which it decreases.
Hindpaw injection of formalin or capsaicin is also used to assess
intense, short-lasting (minutes to tens of minutes) persistent pain. The effect
of formalin is concentration-dependent (Kaneko et al. 2000; Saddi and
Abbott 2000) and is expressed by hindlimb licking and shaking that occur
principally in two phases. The first phase is short (~10 min), followed by
a brief (~5 min) period of relative quiescence, after which a second phase
of hindlimb shaking and licking lasts an additional 50 minutes or so. The
formalin test has also been characterized in infant rats (Abbott and Guy
1995). Capsaicin selectively activates a subset of nociceptors that express
the transient receptor potential vanilloid receptor (TRPV1), an ion channel
that responds to capsaicin, protons, and heat. Intradermal injection of cap-
saicin produces a relatively short-lasting (minutes) but intense pain associ-
ated with hyperalgesia that persists for hours after the capsaicin-produced
pain has resolved.
Joint Inflammation Models
There are physical, chemical, and biologic methods to produce inflam-
matory states that mimic painful conditions of joints. Among physical meth-

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14
APPENDIX A
ods, anterior (cranial) cruciate ligament transection produces instability of
the knee joint and is a common model of osteoarthritis in dogs and rabbits.
Immediately after ligament disruption, animals exhibit joint swelling as well
as a dramatic reduction in weight bearing on the unstable limb although
there will be a return to some degree of weight bearing accompanied by
chronic joint instability.
Chemical methods include the intra-articular injection of inflammo-
gens (e.g., kaolin, carrageenan, iodoacetate, collagenase, urate crystals) to
cause synovitis, varying degrees of cartilage destruction and subsequent
joint swelling, lameness, and decreased activity. Hyperalgesia develops
rapidly (within 4 hours); both inflammation and the duration of inflamma-
tion depend on the agent and dose.
An example of a biologic model is antigen-induced arthritis, which
develops after intra-articular injection of a protein antigen against which
animals have been previously immunized (e.g., methylated bovine serum
albumin). The condition appears only in the injected joints, as soon as 3 to 5
days after injection. The acute form of this arthritis is characterized by joint
and soft-tissue swelling, reduced weight bearing, and altered activity until
the joint swelling declines, typically after 1 week. A longer-lasting chronic
arthritis model (30 to 300 days), established after intra-articular antigen,
involves reactivation of arthritis (arthritis flare) by reinjection 1 month later
(Moran and Bogoch 1999; van den Berg et al. 2007).
Models of rheumatoid arthritis entail activation of an immune response
that targets multiple joints. One example is adjuvant arthritis, a polyarticu-
lar disease that develops 10 to 45 days after intravenous or intraperitoneal
injection of CFA and typically resolves over a month. Another example is
collagen-induced arthritis produced by immunizing animals with type II
collagen; the time course of the resulting arthritis differs between rats and
mice, but onset generally occurs 2 to 4 weeks after immunization. Resolu-
tion of clinical signs occurs in rats after 30 to 45 days, whereas susceptible
mice demonstrate disease 8 to 12 weeks postimmunization. The duration,
severity, and location of arthritis after collagen immunization depends on
the genetic background of the animals being used as well as the source of
the collagen (autologous vs. heterologous) (Griffiths et al. 2007; van den
Berg et al. 2007).
In general, pain associated with inflammatory joint models is assessed
by documenting changes in body weight, joint circumference, joint mobil-
ity, degree of weight bearing, soft tissue swelling, general activity, and gait.
In addition, investigators often quantify latency to withdrawal or vocal-
ization in response to pressure applied across the joint or, as a model of
secondary hyperalgesia, responses to heat or mechanical stimulation of the
hindpaw.

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148 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
Visceral Pain Models
Although once considered models of visceral pain, irritants such as
acetic acid, hypertonic saline, phenylquinone, and others injected intra-
peritoneally do not selectively act on the viscera, and moreover produce
a behavior (writhing) that is inescapable. Accordingly, such models have
fallen into disfavor and have been largely replaced with hollow organ bal-
loon distension, which reproduces in humans the quality, location, and
intensity of actual visceral pain (Ness and Gebhart 1990). Methods for dis-
tension of rat stomach (Ozaki et al. 2002), rat (Ness et al. 2001) and mouse
(Ness and Elhefni 2004) urinary bladder, and rat (Gebhart and Sengupta
1996) and mouse (Christianson and Gebhart 2007) colon have been fully
described.
Hollow organ distension produces several quantifiable responses,
including contraction of skeletal (nonvisceral) muscles (termed the vis-
ceromotor response) and increases in blood pressure and heart rate. Elec-
tromyographic (EMG) recordings of muscle contraction, which require the
surgical implantation of EMG recording electrodes in appropriate muscles,
generally provide the most reliable response measure. Blood pressure and
heart rate measurement require either surgical implantation of an arterial
catheter, which can be difficult to keep patent in rodents, or expensive tele-
metric methods for long-term recording of these measures. These responses
to organ distension are organized in the brainstem (and thus are not simple
nociceptive reflexes) and are best assessed in unanesthetized animals
because anesthetic drugs affect responses (e.g., pressor effects are converted
to depressor effects; Ness and Gebhart 1990).
Because nonulcer dyspepsia, interstitial cystitis/painful bladder syn-
drome, and inflammatory and irritable bowel syndromes are relatively
common human diseases for which management of pain is poor, many
models entail the irritation or inflammation of hollow organs to assess the
mechanisms underlying the hypersensitivity that characterizes these human
disorders.1 The following models have been developed to study these
mechanisms:
• lower esophageal irritation (usually with HCl), stomach ulceration
(acetic acid-produced lesions), and inflammation (oral ingestion of
0.1% iodoacetic acid; Ozaki et al. 2002),
• colon inflammation (e.g., intracolonic trinitrobenzenesulfonic acid
or acetic acid), hypersensitivity in the absence of inflammation
(intracolonic zymosan; Jones et al. 2007),
• urinary bladder inflammation (intraperitoneal administration of
1As indicated in Chapter 2 (see Ontogeny of Pain), organ insult or stress (e.g., maternal
separation) in early life can lead to visceral hypersensitivity in adults (Al-Chaer et al. 2000;
Coutinho et al. 2002; Randich et al. 2006a).

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14
APPENDIX A
cyclophosphamide, which is metabolized to the bladder irritant
acrolein and produces cystitis; Lanteri-Minet et al. 1995), and
• uterine inflammation (Wesselmann et al. 1998).
In unanesthetized rodents, baseline responses to balloon distension are
acquired before organ insult and monitored over time (days to weeks) after
the insult, when they are typically exaggerated (increased) and occur at
reduced response thresholds (i.e., they are hyperalgesic or hypersensitive).
Inflammatory models of the pancreas have also been developed (e.g.,
Vera-Portocarrero et al. 2003). The response measure in these models is
typically mechanical hypersensitivity (e.g., von Frey probing) determined
in the area of referred sensation (thorax and abdominal skin). Similarly, one
response measure in a kidney stone (ureteral calculosis) model is mechani-
cal hypersensitivity, including of the paraspinous muscles. This model is
also associated with episodes of lordosis-like stretching and hunching,
which can be quantified by frequency as well as intensity (Giamberardino
et al. 1995).
Postoperative (Incisional) Pain Models
Models of postoperative pain have revealed that the mechanisms and
subsequent control of postoperative pain differ significantly from those of
inflammatory pain. These models involve an incision of glabrous or hairy
skin of controlled length and depth to determine the relative contributions
of skin, fascia, and underlying muscle to postoperative pain. To eliminate
any possible contribution of infection, the incisions are made under aseptic
conditions. Response measures include both thermal (heat) and mechani-
cal (von Frey probing) hyperalgesia at (primary hyperalgesia) and adjacent
to (secondary hyperalgesia) the incision. An incision of glabrous hindpaw
skin and fascia leads to both thermal and mechanical hyperalgesia that is
maximal within the first 24 to 48 hours after incision and typically lasts 3 to
4 days. When underlying muscle is included in the incision, the duration
(but not the magnitude) of hyperalgesia is usually extended by 1 day.
Orofacial Pain Models
The injection of inflammogens into the temporomandibular joint (TMJ)
or subcutaneous tissues of the face produces models of orofacial pain. Injec-
tion of mustard oil into the TMJ causes rapid onset of swelling and behav-
ioral changes—initially, freezing behavior, followed by a second phase of
active behaviors such as facial rubbing or grooming, chewing movements,
and head shaking. These active behaviors peak at 1.5 to 2 hours and return
to baseline by 5 hours after the injection (Hartwig et al. 2003). Subcutane-
ous formalin injection into the facial whisker pad results in acute onset of

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10 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
facial rubbing in rats that lasts at least 45 minutes. The duration of groom-
ing activity and edema after formalin injection is concentration dependent
(Clavelou et al. 1995). Whisker pad injection of CFA produces a longer-
lasting (2 weeks) thermal and mechanical orofacial hyperalgesia (Morgan
and Gebhart 2008).
Transection or injury of the trigeminal nerve is commonly used to model
neuropathic pain of the face and mouth. Transection of the inferior alveolar
nerve, a branch of the trigeminal nerve, produces mechanical allodynia in
rats after 2 to 3 days (Tsuboi et al. 2004). Similarly, nerve constriction results
in nerve injury and mechanical hyperalgesia. Unilateral chronic constric-
tion injury (CCI) has been used in rats to study orofacial allodynia. After
unilateral loose ligation of the infraorbital nerve, rats develop a biphasic
behavioral response. In the early postligature phase (days 1 to 15), they
demonstrate increased grooming activity at the site of nerve injury but are
hyporesponsive to mechanical stimuli; on postconstriction days 15 to 130,
the rats become hyperresponsive to mechanical stimuli, demonstrating
maximal escape responses to all stimulus intensities. Decreased weight
gain and altered activity also occur in this constriction injury model (Vos
et al. 1994).
Muscle Pain Models
Models of persistent muscle pain include intramuscular injection of
carrageenan or acidic saline. Unilateral injection of carrageenan into the
gastrocnemius muscle of rats produces acute inflammation with edema and
reduced withdrawal latencies in the first 4 to 24 hours. Hyperalgesia also
develops in the contralateral limb 1 to 2 weeks after injection, suggesting
involvement of central nervous system mechanisms. Mechanical and ther-
mal hyperalgesia are dependent on the concentration of carrageenan and
may last 7 to 8 weeks (Radhakrishnan et al. 2003).
Injection of acidic saline in the gastrocnemius produces secondary
mechanical but not thermal hyperalgesia (in tests on the hindpaw). The
magnitude and contralateral spread of hyperalgesia are directly related to
acidity and also depend on the timing of repeated intramuscular injections.
Despite the reductions in mechanical threshold caused by acidic saline
injection, changes do not appear in either behavior (i.e., gait and weight
bearing remain normal, and there is no limb guarding) or muscle histology
(Sluka et al. 2001).
Neuropathic Pain Models
Of the two major classes of clinical pain conditions—those produced
by tissue injury and those produced by nerve injury—the latter for many
years were very difficult to model in animals. The human clinical condition

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11
APPENDIX A
can result from traumatic, metabolic, or drug-induced injury to either the
peripheral nervous system (e.g., diabetic neuropathy, postherpetic neural-
gia, complex regional pain syndrome, or chemotherapy-induced neuropa-
thy) or the CNS (e.g., from multiple sclerosis, stroke-induced destruction
of tissue, or spinal cord injury). Although there have been many attempts
(e.g., the use of streptozotocin to produce an animal model of diabetes and
its associated neuropathy) to model the different clinical conditions, most
studies have built on the principle that neuropathic pain arises from partial
nerve injury (e.g., of a peripheral nerve) or abnormal neuronal activity.
The first model of pain induced by nerve injury (Bennett and Xie
1988) demonstrated that constriction of the sciatic nerve of the rat leads to
persistent pain with significant mechanical and thermal (warm and cold)
hypersensitivity as well as signs of recurrent spontaneous pain. Research-
ers inferred the latter from the animals’ apparent protection of the partially
denervated hindlimb. There have been many variations of this model, and
they are commonly used largely because they are highly reproducible and
involve a relatively short surgical procedure. Among these are models in
which (1) one-half to two-thirds the diameter of the sciatic nerve is cut
(Seltzer et al. 1990), (2) one or two spinal nerves (usually L5 and L6) are
ligated and/or cut just distal to the dorsal root ganglion (Kim and Chung
1992), and (3) two of the three branches of the sciatic nerve are cut distal
to its trifurcation (Decosterd and Woolf 2000). In general, these models
are associated with a more pronounced mechanical allodynia than heat
hyperalgesia; cold hypersensitivity is prominent. These models were devel-
oped in the rat and, importantly, several have been adapted for the mouse,
which has proven very valuable for the study of the genetic basis of differ-
ent nerve injury-induced pain conditions (Malmberg and Basbaum 1998;
Shields et al. 2003).
Although spontaneous pain may be associated with these models (see
below), this is not readily apparent and is certainly difficult to document.
There is rarely any significant change in behavior or weight loss that might
indicate ongoing pain. Thus testing of the animals typically involves assess-
ment of changes in mechanical paw withdrawal thresholds (using von
Frey-like nylon monofilaments or the Randall Selitto apparatus) and paw
withdrawal latencies for assessment of heat hyperalgesia. Cold hypersen-
sitivity is very difficult to assess in rodents. Some laboratories rely on the
evaporation of acetone applied to the affected hindpaw; the endpoint is
shaking of the paw. Responses on a single cold plate are often used, but
typically very cold temperatures are necessary in order to generate any
behavioral response. For this reason, better results are reported using a two-
plate method in which an animal can escape to the plate that is less cold.
The reliability of these different approaches to modeling neuropathic
pain is evident primarily from the demonstration that drugs that are effective
(or not) in the clinic for neuropathic pain are effective in the animal mod-

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12 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
els. For example, many anticonvulsant drugs, which either block sodium
channels or enhance GABAergic inhibitory tone, are effective in the animal
models and also are the mainstay for neuropathic pain relief in humans.
In contrast, there is general agreement that nonsteroidal anti-inflammatory
drugs are quite ineffective in humans with neuropathic pain, and the same
is true in the animal models. Opioids also are less effective in neuropathic
pain models than in inflammatory models, and this is commonly observed
in the clinic.
As noted above, one of the problematic adverse side effects of chemo-
therapy treatment for cancer pain is the development of a profound periph-
eral neuropathy with mechanical allodynia, thermal hypersensitivity, and
ongoing, often burning pain. In recent years several laboratories have devel-
oped neuropathic pain models based on treatment with vincristine or taxol;
the treatment typically involves weeks of drug administration to gradually
produce in the animals a significant mechanical and thermal hypersensitiv-
ity to both warm and cold stimuli (the hypersensitivity disappears when the
drug treatment ends). Very recently, a somewhat comparable condition has
been reported following the administration of antiretroviral drugs, which are
used in the treatment of HIV and are also often associated with the develop-
ment of severe neuropathic pain.
The drive to model as closely as possible the clinical conditions in
which pain occurs in humans has led to the development of animal models
to reproduce the conditions for neuropathic pains associated with spinal or
foraminal stenosis and disk herniations, many of which are considered criti-
cal to the development of chronic back pain. In these animal models, two
L-shaped rods are placed unilaterally into the intravertebral foramin, one at
L4 and the other at L5 (Hu and Xing 1998). The rods remain in place from
1 to 14 days, after which behavioral, electrophysiological, and anatomical
studies are performed to document mechanical and thermal hypersensitiv-
ity and to elucidate the underlying causes of the pain. To what extent the
pain that results from this condition reflects the compression and associated
block of activity of subpopulations of afferent nerve fibers or whether there
is an active inflammatory process that activates nerve fibers is a critical
focus of study. In this regard it is of interest that the application of a variety
of cytokines to the peripheral nerve (Sorkin et al. 1997) or even of autolo-
gous nucleus pulposus to the DRG of the rabbit (Cavanaugh et al. 1997)
can recapitulate features of neuropathic pain.
Cancer Pain
As cancer pain is one of the most severe and most difficult pains to treat
in humans, particularly in late stages of the disease, it is perhaps surprising
that animal models of pain associated with cancer have only recently been
developed. In part, the paucity of models reflects the difficulty of creat-

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APPENDIX A
ing a reliable and reproducible condition. The last decade, however, has
seen the development of such models in both rats and mice (for a review,
Pacharinsak and Beitz 2008). Rather than studying the pain associated with
the destruction of a particular organ, attention has focused on the pain that
develops after metastasis of tumors to, for example, bone, which is among
the most painful conditions. To this end, Mantyh and colleagues (Schwei
et al. 1999) initially described a model that involved implanting osteolytic
sarcoma cells in the femur of a mouse and sealing the femur to restrict
tumor growth. Pathological studies as the tumor developed revealed char-
acteristic osteoclast destruction of bone, presumably in the relatively acidic
environment that promotes osteoclast function. Over time there was bone
destruction concurrent with the development of a clear hypersensitivity to
mechanical probing of the affected limb. Importantly, this model has proven
very useful for the testing of novel pharmaceuticals for the treatment of pain
associated with tumor metastasis to bone. Ongoing studies are directed at
assessing the nature of the pathology that generates the pain. It was origi-
nally assumed that such cancer pains are largely inflammatory in nature,
but animal studies indicate that there is a nerve injury-associated compo-
nent as well. The peripheral nerve endings of fibers that innervate bone
are unquestionably involved and these likely contribute to the mechanical
hypersensitivity and ongoing pain that develop.
More recently, attention has turned to pains likely associated with the
more traditional models of cancer that are used to study the biological basis
for the generation and treatment of tumor development. For example, Lind-
say and colleagues (2005) used a well-studied transgenic model of pancre-
atic cancer (produced by expression of the simian virus 40 large T antigen
under control of the rat elastase-1 promoter) to monitor behavioral changes
that might indicate ongoing pain. Interestingly, they found that when there
were cellular changes characteristic of an inflammatory response, the mice
did not manifest any behavior indicative of ongoing pain or hypersensitiv-
ity. A comparable magnitude of inflammatory changes in the skin would
typically be associated with clear mechanical and thermal hypersensitivity.
Signs of pain, including hunching and vocalization, eventually occurred at
16 weeks of age, at which point the pancreatic cancer was severe. Whether
there is a masking of pain in the early stages of the disease remains to be
determined, but this model illustrates that the mechanism(s) of development
of the pains associated with different types of cancer are not the same and
likely have multiple etiologies.
Spontaneous Pain
Most of the persistent pain models described above measure pain pro-
voked by thermal, mechanical, or (less frequently) chemical stimuli. Many
of these models are also presumed to be associated with ongoing, spontane-

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14 RECOGNITION AND ALLEVIATION OF PAIN IN LABORATORY ANIMALS
ous pain, which frequently manifests as reduced activity. For example, in
inflammatory visceral pain models, mice and rats with inflamed stomachs,
bladders, or colons tend to sit quietly in their cages and do not explore in
open field tests (although they do not become difficult to handle and they
continue to eat and gain weight). Similarly, animals with inflamed or incised
hindpaws commonly guard the paw by raising it above the floor and hold-
ing it in an unnatural posture. In tests these animals will not readily bear
weight on the affected hindpaw until resolution of the insult. In both of the
above examples, and in inflammatory models in general (e.g., joint, muscle,
orofacial), the effects of the inflammation or incision are reversible and rela-
tively short-lived (days to weeks). Whether ongoing pain at rest is present
in these models is unknown. In analogous inflammatory and postsurgical
circumstances in humans, pain at rest is either minimal or acceptable, but,
as in these animal models, hypersensitivity and pain can be easily provoked
by certain stimuli (e.g., forced movement, application of noxious stimuli).
In models of peripheral neuropathic pain, in which mechanical allo-
dynia is present, nail growth and changes in hindpaw temperature (indica-
tive of altered sympathetic efferent function) along with limb guarding
are common. Cancer pain models are also associated with increasing dis-
comfort and spontaneous pain as tumor burden increases. In both of these
models, the effects of either nervous system insult or cancer are long-lasting
(weeks to months) and minimally reversible; therefore, animals are gener-
ally euthanized according to humane endpoint principles.
Readers are urged to consult Chapter 5 for an extensive discussion of
humane endpoints and Chapter 4 for an analysis of the ethical conflicts
associated with research using persistent pain models.
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